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Molecular Cancer Therapeutics
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Research Articles: Therapeutics, Targets, and Development

Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model

Akihiko Miyanaga, Akihiko Gemma, Rintaro Noro, Kiyoko Kataoka, Kuniko Matsuda, Michiya Nara, Tetsuya Okano, Masahiro Seike, Akinobu Yoshimura, Akiko Kawakami, Haruka Uesaka, Hiroki Nakae and Shoji Kudoh
Akihiko Miyanaga
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Akihiko Gemma
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Rintaro Noro
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Kiyoko Kataoka
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Kuniko Matsuda
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Michiya Nara
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Tetsuya Okano
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Masahiro Seike
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Akinobu Yoshimura
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Akiko Kawakami
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Haruka Uesaka
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Hiroki Nakae
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Shoji Kudoh
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DOI: 10.1158/1535-7163.MCT-07-2140 Published July 2008
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    Figure 1.

    A, IC50 values for a panel of 16 NSCLC cell lines responding to TSA treatment as determined via MTT assay. Cell lines were classified as highly sensitive (IC50 ≤ 1 μmol/L) and resistant (IC50 < 15 μmol/L) to TSA.B, IC50 values for a panel of 16 NSCLC cell lines responding to vorinostat treatment as determined via MTT assay. Cell lines were classified as highly sensitive (IC50 ≤ 3 μmol/L) and resistant (IC50 < 15 μmol/L) to vorinostat. C, correlation between the responsiveness to TSA and vorinostat in a panel of 16 NSCLC cell lines (Spearman rank correlation r = 0.949, P < 0.0001).

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    Figure 2.

    Contribution of the nine genes associated with HDAC inhibitor sensitivity. It was calculated based on the independent Partial Least Squares analysis.

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  • Table 1.

    Factors associated with TSA sensitivity based on expression profiles, sensitivity, and pathway analyses in the 16 NSCLC cell line panel and their functions

    Probe set IDGene symbolGene titleGenes incorporated by pathway analysisCorrelation coefficients
    201064_s_atPABPC4Poly(A) binding protein, cytoplasmic 4 (inducible form)
    201737_s_atMARCH6Membrane-associated ring finger (C3HC4) 6
    209339_atSIAH2Seven in absentia homologue 2 (Drosophila)
    212887_atSEC23ASec23 homologue A (Saccharomyces cerevisiae)+−0.734
    214857_atC10orf95Chromosome 10 open reading frame 95
    217100_s_atUBXD7UBX domain containing 7
    201762_s_atPSME2Proteasome (prosome, macropain) activator subunit 2 (PA28 β)+−0.683
    201919_atSLC25A36Solute carrier family 25, member 36
    201993_x_atHNRPDLHeterogeneous nuclear ribonucleoprotein D like+0.678
    202731_atPDCD4Programmed cell death 4 (neoplastic transformation inhibitor)+0.724
    208799_atPSMB5Proteasome (prosome, macropain) subunit, β type, 5+−0.688
    208912_s_atCNP2′,3′-cyclic nucleotide 3′ phosphodiesterase
    209149_s_atTM9SF1Transmembrane 9 superfamily member 1+−0.672
    209150_s_atTM9SF1Transmembrane 9 superfamily member 1+−0.672
    210519_s_atNQO1NAD(P)H dehydrogenase, quinone 1+−0.690
    211730_s_atPOLR2LPolymerase (RNA) II (DNA directed) polypeptide L, 7.6-kDa polymerase (RNA) II (DNA directed) polypeptide L, 7.6 kDa
    212082_s_atMYL6Myosin, light polypeptide 6, alkali, smooth muscle and nonmuscle+−0.718
    219717_atFLJ20280Hypothetical protein FLJ20280
    220200_s_atSETD8SET domain containing (lysine methyltransferase) 8
  • Table 2.

    Validation of predictive performance of the nine genes by examining the SVM value in an independent set of nine NSCLC cell lines

    Cell linesIC50 (TSA)IC50 (vorinostat)Predicted classTrue class (TSA)True class (vorinostat)
    1LCI-sq0.192.14SensitiveHighly sensitiveHighly sensitive
    2VMRC-LCD0.270.87SensitiveHighly sensitiveHighly sensitive
    3Lu650.343.74SensitiveHighly sensitiveIntermediate sensitive
    4LCOK0.523.66SensitiveHighly sensitiveIntermediate sensitive
    5NCI-H16500.899.37SensitiveHighly sensitiveIntermediate sensitive
    6LC1F1.264.82SensitiveIntermediate sensitiveIntermediate sensitive
    7NCI-H19751.563.96SensitiveIntermediate sensitiveIntermediate sensitive
    8NCI-H4410.778.30SensitiveHighly sensitiveIntermediate sensitive
    9Calu-60.582.10SensitiveHighly sensitiveHighly sensitive
    • NOTE: Cell lines were classified as highly sensitive (IC50 ≤ 1 μmol/L), intermediate sensitive (1 μmol/L < IC50 ≤ 15 μmol/L), and resistant (IC50 < 15 μmol/L) to TSA. In relation to response to vorinostat, cell lines were classified as highly sensitive (IC50 ≤ 3 μmol/L), intermediate sensitive (3 μmol/L < IC50 ≤15 μmol/L), and resistant (IC50 < 15 μmol/L).

Additional Files

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  • Supplementary Material, Miyanaga et al

    Files in this Data Supplement:

    • Supplementary Fig. S1
    • Supplementary Fig. S2
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Molecular Cancer Therapeutics: 7 (7)
July 2008
Volume 7, Issue 7
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Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model
Akihiko Miyanaga, Akihiko Gemma, Rintaro Noro, Kiyoko Kataoka, Kuniko Matsuda, Michiya Nara, Tetsuya Okano, Masahiro Seike, Akinobu Yoshimura, Akiko Kawakami, Haruka Uesaka, Hiroki Nakae and Shoji Kudoh
Mol Cancer Ther July 1 2008 (7) (7) 1923-1930; DOI: 10.1158/1535-7163.MCT-07-2140

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Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model
Akihiko Miyanaga, Akihiko Gemma, Rintaro Noro, Kiyoko Kataoka, Kuniko Matsuda, Michiya Nara, Tetsuya Okano, Masahiro Seike, Akinobu Yoshimura, Akiko Kawakami, Haruka Uesaka, Hiroki Nakae and Shoji Kudoh
Mol Cancer Ther July 1 2008 (7) (7) 1923-1930; DOI: 10.1158/1535-7163.MCT-07-2140
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